Project 2: Progesterone Regulation of Synaptic Plasticity & Memory. In this Program Project, we jointly hypothesize that the sex steroid hormone progesterone promotes the brain's molecular, synaptic, cellular, and behavioral plasticity and reduces its vulnerability to the development of Alzheimer's disease (AD). We further hypothesize that the reproductive endocrine status, duration of ovariprivation and presence of AD related pathology regulates the plasticity response to ovarian steroids. Realizing the potential neural benefits of hormone therapy is constrained, at least in part, by our currently limited knowledge of the (1) basic neurobiology of progesterone, (2) the neural response to clinically relevant progestogens, (3) the complex modulatory interactions between progesterone and estrogen and (4) the impact of extended ovarian hormone privation and AD neuropathology on the brain's responsiveness to progesterone and estrogen. Our component of the Program Project is directed at investigating the effects of progesterone, as well as the interactions between estrogen, progesterone, and progesterone metabolites on biochemical, cellular and behavioral models of memory function in adult and aging rodent models. At the biochemical level, we will evaluate the acute and chronic effects of progesterone on the activation of the MAP kinase pathway and the phosphorylation of AMPA and NMDA receptors in hippocampus and cortex, which represent critical steps in synaptic plasticity. Parallel experiments at the cellular level will evaluate the acute and chronic effects of progesterone on synaptic transmission and synaptic plasticity (long-term potentiation and long-term depression) in the CA1 hippocampal in vitro slice preparation. Finally, the acute and chronic effects of progesterone will be determined on delayed conditioned taste aversion learning and context/tone fear conditioning in order to correlate effects at the molecular/cellular levels with those at the behavioral level. These same parameters will be evaluated in new animal models shared by the other investigators of the Program Project: a model of the peri-menopausal and menopausal period in rats as well as in a mouse model of Alzheimer's disease. The results obtained from these studies should provide critical information to understand the complex interactions between female sex hormones and processes underlying learning and memory and their modifications during postmenopausal period and aging and age-related disorders.